Perioperative morbidity and mortality due to heart disease are important complications of non-cardiac surgery. In the United States approximately 27 million patients undergo non-cardiac surgery annually, with 50 thousand suffering a post- or intra-operative myocardial infarction (MI). The problem is also highly prevalent among our nation?s veterans. Specifically, the Veterans Health Administration performs about 400,000 surgical procedures per year, and data derived from the Veterans Affairs Surgical Quality Improvement Program (VASQIP) indicate that major adverse cardiovascular events (MACE) after non-cardiac surgeries occur in approximately 5%, while another study indicates that myocardial injury indicated by asymptomatic post- operative troponin elevation, a major risk factor for post-operative mortality, occurs in 13.9% of veterans undergoing non-cardiac surgery. On the other hand physical activity is one of the most powerful modifiers of cardiovascular risk, with proven benefits both for those with healthy hearts and for those with diseased hearts. Skeletal muscles are critical for mobility, but there is also an emerging understanding that they produce and secrete cytokines, termed ?myokines?, which mediate local and systemic changes in order to promote exercise tolerance and overall health. We recently demonstrated that the myokine musclin is upregulated in response to physical activity and augments physical endurance. Our preliminary data also indicate that musclin production drives the myocardial energetic adaptation necessary to increase cardiac stress resistance. Based on these findings we propose that musclin upregulation is critical for exercise-induced cardiac conditioning and that this effect utilizes molecular pathways that, once defined, may be harnessed for therapeutic benefit. Musclin, also known as osteocrin, has high homology to the cardiac natriuretic peptides (NP) with comparable affinity for the clearance receptor, NPRC, but low affinity for the guanylyl cyclase-coupled receptors, NPRA and NPRB. Through competitive interference for elimination at NPRC, musclin increases the local concentration of NPs and augments their effect on synthesis of cyclic guanosine monophosphate (cGMP) - a critical intracellular messenger. This project will use unique genetic mouse models and specially developed bioassays to determine the molecular mechanisms by which musclin integrates skeletal muscle and myocardial adaptive exercise responses to promote the energetic remodeling necessary for enhanced cardiac performance and stress resistance. Further, the proposal will assess the ability of synthetic musclin infusion to mimic some of the benefits triggered by exercise and thereby reduce vulnerability of the heart to injury. Findings from this study are expected to provide a foundation for development of novel cardioprotective strategies for high-risk patients, such as those for whom exercise is not possible or well-tolerated due to illnesses or injuries, and who require stressful surgeries or interventions.